1. Field of the Invention
The present invention is broadly directed to structure-based combinatorial libraries, especially a group of compounds containing the functional group minima in picornaviruses including poliovirus and rhinovirus. The libraries provided by the present invention contain candidates of anti-picornaviral capsid-binding compounds which can be therapeutically effective in antiviral treatments.
2. Description of Related Art
Picornaviruses represent a very large virus family of small ribonucleic acid-containing viruses responsible for many serious human and animal diseases (Rueckert, R. R. Virology, 2nd ed. (Fields, B. N. et al., eds.) Raven Press, Ltd., New York, p. 508-548 (1982)). Picornaviruses include four major groups: enteroviruses, rhinoviruses, cardioviruses and apthoviruses. Enteroviruses include polioviruses, Coxsackieviruses, echoviruses, and four numbered enteroviruses.
Poliovirus is the etiologic agent of the disease poliomyelitis in humans, and there are three known serotypes of the virus. The oral poliovaccine, typically given to children, is a mixture of the Sabin strain of the three serotypes of the virus. Mahoney and Leon (the parent strains of Sabin 1 and 3, respectively) are human neurovirulent strains of poliovirus. The oral poliovirus vaccine is safe and effective, yet has two limitations. First, the vaccine is unstable; current vaccines are inactivated by relatively brief (less than 24 hours) exposure to temperatures of 37xc2x0 C., necessitating transport in a frozen state from the site of manufacture to the locale where they are administered. Second, the vaccine occasionally reverts to virulence in vaccine recipients; the reverted virulent virus may also be passed to other individuals who come into contact with the recipient in whom the vaccine has reverted.
The human rhinoviruses consist of at least 100 serotypes and are the primary causative agents of the common cold. Because of the large number of serotypes, development of a vaccine is problematic; antiviral agents may therefore be the best approach to treatment. The Coxsackieviruses (24 group A serotypes, 6 group B serotypes), echoviruses (34 serotypes) and human enteroviruses (four serotypes), are associated with a wide range of human diseases including summer flus, diarrhea, meningitis, hepatitis, pneumonia, myocarditis, pericarditis, and diabetes (Melnick, J. L. Virology, 2nd ed. (Fields, B. N. et al., eds.) Raven Press, Ltd., New York p549-605). These infections occur sporadically in the general population, but are becoming more common among children in day care and their parents and siblings. Other important members of the picornavirus family include human hepatitis A virus, Theiler""s murine encephalomyelitis virus, foot-and-mouth disease virus, and mengovirus.
Several crystal structures of poliovirus and rhinovirus capsids have been solved by X-ray diffraction. The X-ray structures of poliovirus P1/Mahoney (Hogle, J. M., et al., Science 229:1358 (1985)); poliovirus P3/Sabin (Filman, D. J., et al., EMBO J. 8:1567 (1989)); rhinovirus 14 (Rossman, M. G., et al., Nature 317:145 (1985)); rhinovirus 1A (Smith, T. J., et al., Science 233:1286 (1986)); and rhinovirus 16 (Oliveira, M. A., et al., Structure 1(l):51-68 (1993)) are strikingly similar, although poliovirus and the rhinoviruses are currently classified in different genuses. Experimental results have revealed that there is a binding site in the poliovirus structure which usually binds a lipid-like molecule (Filman, D. J., et al., EMBO J. 8:1567 (1989)). When a drug is bound in this site in poliovirus or rhinovirus, the virus is stabilized, and in some cases. infection is prevented (McSharry, J. J., et al., Virology 97:307 (1979); Smith, T. J., et al., Science 233:1286 (1986); reviewed in Zhang, A., et al., Virology, 3:453 (1992)). The functional group minima of picornavirus capsid proteins have been determined via computational analysis of a ligand binding site (D. Joseph-McCarthy et al., 1997, Proteins 29:32).
The existing drugs which are used against the viruses described above are only moderately effective. Available drugs are typically effective against only a limited subset of the rhinovirus serotypes. In general, the available drugs have either failed to demonstrate sufficient prophylactic effect or are converted in the body into inactive metabolites. Furthermore, current drugs have all been derived from the same parent compound that was found through large-scale random screening of known chemicals for activity against the virus, a very expensive and time-consuming process. A need continues for additional drugs with better efficacy, and with efficacy against pathogenic picornaviruses.
It is an object of the invention to provide a composition which is a candidate anti-picornavirus capsid-binding compound.
It is another object of the invention to provide a library of compositions useful for screening for anti-picornavirus capsid-binding compounds.
It is yet another object of the invention to provide methods of making the compositions and the libraries of the compositions provided in the present invention.
These and other objects of the invention are provided by one or more of the embodiments provided below.
In one embodiment of the invention there is provided a composition which comprises two aromatic monomers and a spacer monomer, wherein the two aromatic monomers are covalently linked through X to the spacer monomer, where X is S or O, and the aromatic monomer and the spacer monomer are functional group minima of picornaviruses.
In another embodiment of the invention there is provided a method of making the composition provided by the present invention which comprises the steps of mixing equimolar amounts of one or more aromatic monomers to form a mixture, incubating a solution of one or more dibromide spacer monomers with the mixture to form an organic phase, washing and concentrating the organic phase.
The present invention provides libraries of compounds which are candidates for anti-picornaviral capsid-binding compounds. Such compounds provide therapeutic benefits in anti-picornaviral treatment. The present invention also provides methods for making such libraries.